Overview

Also Known As:HdhQ111 KI

This strain is currently unavailable due to replenishing of cryopreserved stocks. Interested customers who register interest will be contacted when the strain is again available.

These Htt knock-in mice exhibit a Huntington's-like pathology.

Donating Investigator

IMR Colony, The Jackson Laboratory

Genetic overview

Genetic Background	Generation
000664 C57BL/6J

Htt^tm5Mem

Allele Type	Gene Symbol	Gene Name
Targeted (Humanized sequence)	Htt	huntingtin

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Research Applications

Neurobiology Research
Mouse/Human Gene Homologs

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Details

Detailed Description

This strain carries 111 CAG repeat units in the first exon of the endogenous Htt gene. Huntington's-like pathology is seen in the striatum, including nuclear localization of the protein, N-terminal inclusions, and insoluble aggregate formation. Instability of the length of the CAG repeat between generations is seen. Expression of the phenotype occurs earlier than in Htt^tm4, (Stock No. 003455).

In an attempt to offer alleles on well-characterized or multiple genetic backgrounds, alleles are frequently moved to a genetic background different from that on which an allele was first characterized. This is the case for the strain above. It should be noted that the phenotype could vary from that originally described. We will modify the strain description if necessary as published results become available.

Development

A targeting vector containing neomycin resistance and herpes simplex virus thymidine kinase genes and 111 CAG repeat units was used to disrupt exon 1. The construct was electroporated into 129 derived R1 embryonic stem (ES) cells. Correctly targeted ES cells were injected into recipient blastocysts. The resulting chimeric male animals were crossed to CD1 mice, and then backcrossed to C57BL/6J for 6 generations.

Control Suggestions

000664 C57BL/6J

Additional Information

Considerations for Choosing Controls

Selected References

Wheeler VC; Auerbach W; White JK; Srinidhi J; Auerbach A; Ryan A ; Duyao MP ; Vrbanac V ; Weaver M ; Gusella JF ; Joyner AL ; MacDonald ME. 1999. Length-dependent gametic CAG repeat instability in the Huntington's disease knock-in mouse. Hum Mol Genet 8(1):115-22PubMed: 9887339 MGI: J:52440

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Genetics

Htt^tm5Mem

Allele Symbol: Htt^tm5Mem

Allele Name	targeted mutation 5, Marcy E MacDonald
Allele Type	Targeted (Humanized sequence)
Allele Synonym(s)	Hdh^Q111
Gene Symbol and Name	Htt, huntingtin
Gene Synonym(s)
Promoter	Htt, huntingtin, mouse, laboratory
Strain of Origin	(129X1/SvJ x 129S1/Sv)F1-Kitl⁺
Chromosome	5
Molecular Note	This allele carries 109 CAG repeat units, with 111 glutamines, in the first exon of the endogenous gene. It is a derivative of Htt^tm8 in which the neo cassette has been removed via cre-mediated recombination.
Mutations Made By	Dr. Marcy MacDonald, Massachusetts General Hospital

Disease/Phenotype

Disease Terms

Model with phenotypic similarity to human disease where etiologies involve orthologs. Human genes are associated with this disease. Orthologs of those genes appear in the mouse genotype(s).

Huntington's disease

Research Areas By Phenotype

This mouse can be used to support research in many areas including:

Genotype: Htt^tm5Mem related

Neurobiology Research
- Cortical Defects
- Neurodegeneration
- Huntington's disease
Mouse/Human Gene Homologs
- Huntington's disease (chorea)

Mammalian Phenotype Terms by Genotype

The following phenotype information is associated with a similar, but not exact match to this JAX^® Mice strain

Genotype: Htt^tm5Mem/Htt^tm5Mem
STOCK Htt/J

behavior/neurological phenotype

abnormal motor coordination/balance
- homozygous males perform better than wild type controls on rotarod test
- homozygous females perform slightly worse than controls at the oldest ages

growth/size/body region phenotype

decreased body weight
- decrease in body weight is decreased by 28 weeks in both genders

mammalian phenotype

behavior/neurological phenotype
- Normal - mice do not exhibit hypoactivity or rearing in open field test that differs significantly from controls
- Normal - stride length, splay length and base are similar to controls
- Normal - mice do not exhibit a deterioration in grip strength as compared to controls
- Normal - dark preference in dark/light choice test is similar to controls
- Normal - mice do not exhibit a decrease in climbing activity

nervous system phenotype
- Normal - mice do not exhibit alterations in startle reflex or in prepulse inhibition

Genotype: Htt^tm5Mem/Htt^tm5Mem
involves: 129S1/Sv * 129X1/SvJ * CD-1

behavior/neurological phenotype

abnormal behavior
- onset of persistent rubbing and irritability from 12 to 16 months of age

hypoactivity
- onset of hypoactivity from 12 to 16 months of age

tremors
- onset of trembling from 12 to 16 months of age

limb grasping
- onset of clasping behavior from 12 to 16 months of age

nervous system phenotype

abnormal nervous system physiology
- between 8 and 12 weeks of age, striatal mitochondria develops resistance to calcium, becoming equally sensitive to calcium as cortical mitochondria, whereas in wild-type, striatal mitochondria is more sensitive to calcium than cortical mitochondria

abnormal striatum morphology
- the levels of both the endogenous excitotoxin quinolinic acid (QUIN) and its bioprecursor, 3-hydroxykynurenine (3-HK) are increased in the striatum beginning at 15 months of age, similarly to that seen in Huntington disease patients

abnormal medium spiny neuron morphology
- exhibit relocation of the mutant protein to the nucleus in medium sized spiny neurons and much later, the formation of morphologic nuclear inclusions (at around 10 months) and insoluble aggregate that are hallmarks of Huntington's Disease in humans

abnormal cerebral cortex morphology
- QUIN and 3-HK levels are increased in the cortex beginning at 15 months of age, as seen in patients with Huntington disease

neuronal intranuclear inclusions
- observed at 10 months

Genotype: Htt^tm5Mem/Htt⁺
involves: 129S1/Sv * 129X1/SvJ * CD-1

nervous system phenotype

abnormal medium spiny neuron morphology
- han in homozygotes
- exhibit relocation of the mutant protein to the nucleus in medium sized spiny neurons and much later, the formation of morphologic nuclear inclusions and insoluble aggregate that are hallmarks of Huntington's Disease in humans, although at a slower rate than in homozygotes

abnormal striatum morphology

neuronal intranuclear inclusions

References

Wheeler VC; Auerbach W; White JK; Srinidhi J; Auerbach A; Ryan A ; Duyao MP ; Vrbanac V ; Weaver M ; Gusella JF ; Joyner AL ; MacDonald ME. 1999. Length-dependent gametic CAG repeat instability in the Huntington's disease knock-in mouse. Hum Mol Genet 8(1):115-22PubMed: 9887339 MGI: J:52440

Additional References

Wheeler VC; White JK; Gutekunst CA; Vrbanac V; Weaver M; Li XJ; Li SH; Yi H; Vonsattel JP; Gusella JF; Hersch S; Auerbach W; Joyner AL; MacDonald ME. 2000. Long glutamine tracts cause nuclear localization of a novel form of huntingtin in medium spiny striatal neurons in HdhQ92 and HdhQ111 knock-in mice. Hum Mol Genet 9(4):503-13PubMed: 10699173 MGI: J:60937
White JK; Auerbach W; Duyao MP; Vonsattel JP; Gusella JF; Joyner AL ; MacDonald ME. 1997. Huntingtin is required for neurogenesis and is not impaired by the Huntington's disease CAG expansion. Nat Genet 17(4):404-10PubMed: 9398841 MGI: J:44391

Additional - Htt^tm5Mem related

Technical Support

CONTACT TECHNICAL SUPPORT

Genotyping Protocols
- Standard PCR:Laragen
- Standard PCR:Htt
- Genotyping resources and troubleshooting
Breeding Considerations

When maintaining a live colony, these mice are bred as homozygotes.
- Additional Breeding and Husbandry Support
Citation
When using the HdhQ111 KI mouse strain in a publication, please cite the originating article(s) and include JAX stock #003598 in your Materials and Methods section.

Strain Interest Registration

Please fill out the form below to indicate your interest in purchasing this JAX®Mice strain.
This information helps us manage the colony build and better meet the broad needs of the research community.
Please send any technical questions to Technical Support.

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Licensing Information

Phone: 207-288-6470

Email: TechTran@jax.org

Also Known As:HdhQ111 KI

Donating Investigator

Genetic overview

Research Applications

Detailed Description

Development

Control Suggestions

Additional Information

Selected References

Htttm5Mem

Allele Symbol: Htttm5Mem

Disease Terms

Model with phenotypic similarity to human disease where etiologies involve orthologs. Human genes are associated with this disease. Orthologs of those genes appear in the mouse genotype(s).

Research Areas By Phenotype

This mouse can be used to support research in many areas including:

Genotype: Htttm5Mem related

Mammalian Phenotype Terms by Genotype

Genotype: Htttm5Mem/Htttm5MemSTOCK Htt/J

behavior/neurological phenotype

growth/size/body region phenotype

mammalian phenotype

Genotype: Htttm5Mem/Htttm5Meminvolves: 129S1/Sv * 129X1/SvJ * CD-1

behavior/neurological phenotype

nervous system phenotype

Genotype: Htttm5Mem/Htt+involves: 129S1/Sv * 129X1/SvJ * CD-1

nervous system phenotype

References

Additional References

Additional - Htttm5Mem related

Genotyping Protocols

Breeding Considerations

Citation

Strain Interest Registration

Contact Information

Interest

Terms Of Use

Licensing Information

Htt^tm5Mem

Allele Symbol: Htt^tm5Mem

Genotype: Htt^tm5Mem related

Genotype: Htt^tm5Mem/Htt^tm5Mem
STOCK Htt/J

Genotype: Htt^tm5Mem/Htt^tm5Mem
involves: 129S1/Sv * 129X1/SvJ * CD-1

Genotype: Htt^tm5Mem/Htt⁺
involves: 129S1/Sv * 129X1/SvJ * CD-1

Additional - Htt^tm5Mem related